BJS Academy is delighted to host the second edition of the textbook ‘basic concepts of fluid and electrolyte therapy’, by Lobo, Lewington and Allison.

The authors have kindly divided the book into four easily digestible sections, and then some multiple choice questions at the end.

Surgeons sometimes focus a little too much on the technical aspects of their work, but without a sound knowledge of fluid and electrolyte management, their efforts in the operating theatre may easily be undone.

All surgeons will benefit from reading this book and gaining an understanding of how best to optimise fluid management in their patients.

Jonothan Earnshaw

Director, BJS Academy

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The authors have made every effort to ensure that drug dosages in this book are in accordance with current recommendations and practice at the time of publication.

However, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions.

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Table of Contents

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PREFACE

The first edition of this book was published in 2013 with the aim of improving understanding and clinical practice in the field of fluid and electrolyte therapy. Studies at that time suggested that, even though fluid and electrolyte preparations are the most commonly prescribed medications in hospitals, man- agement of fluid and electrolyte disorders was suboptimal, possibly due to inadequate teaching, causing avoidable morbidity and even mortality. It should not be forgotten that fluid therapy, like other forms of treatment, has the capacity to do harm as well as good unless administered with care and based on sound knowledge.

A second edition was felt appropriate in the light of further advances in knowledge and practice over the last 9 years. We have updated the book, adding new chapters, figures, tables and flow charts to help the reader. New chapters include Ageing and Fluid Balance, Chronic Kidney Disease, Fluid Overload and the De-escalation Phase, and Perioperative Fluid Therapy and Outcomes. We have also tried to maintain consistency with published national and international guidelines, where available. References have now been cited in the text. To limit the number of references, we have tried, as far as possible to cite impor-tant review articles from which original studies may be sourced. However, relevant original works have been referred to when appropriate. We have included multiple choice questions so that readers may test their knowledge after reading the book.

The subject of fluid balance in paediatrics is not addressed and this book should be regarded as relevant to adults only. It is still not our intention to write a comprehensive textbook dealing with complex prob- lems, but to provide a basic hand-book for students, nurses, trainee doctors and other health care pro- fessionals to help them to understand and solve some of the most common practical problems they face in day to day hospital practice. We hope that it will also stimulate them to pursue the subject in greater detail with further reading and practical experience. In difficult cases, or where there is uncer- tainty, trainee health care professionals should never hesitate to ask for advice from senior and expe- rienced colleagues.

Dileep N. Lobo

Andrew J. P. Lewington

Simon P. Allison

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List of Abbreviations

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Chapter 1: Normal Anatomy and Physiology of the body fluids

INTRODUCTION

When primitive marine unicellular organisms evolved into multicellular forms and emerged onto land, they faced several physiological challenges including the maintenance of water and salt balance in an environment low in both. Rather than being surrounded by an external sea, they carried with them their own internal sea or extracellular fluid (ECF), in which their cells could bathe in a constant chemical environment, which the great French physiologist Claude Bernard called the ‘milieu interieur‘ ^1,2. In this environment the cells retain their energy consuming and primeval capacity to pump sodium out and to retain potassium to neutralise the negative charges of proteins and other ions.

While fluid balance is usually considered as that between the body and its environment, i.e. external balance, disease also affects the internal balance between the various body fluid compartments, e.g. between the intravascular and interstitial components of the ECF, between the intracellular fluid (ICF) and the ECF, and between the ECF and the gut and other internal spaces^3,4.

NORMAL ANATOMY AND PHYSIOLOGY

Water comprises about 60% of the body weight of an average adult, although the percentage is lower in those with obesity, since adipose tissue contains less water than lean tissue⁵. As shown in Figs. 1.1 and 1.2, the total body water is divided functionally into the extracellular and the intracellular fluid spaces (ECF≈20% body weight and ICF≈40% body weight) separated by the cell membrane with its active sodium pump, which ensures that sodium remains largely in the ECF. The cell, however, contains large anions such as protein and glycogen, which cannot escape and, therefore, draw in potassium ions to maintain electrical neutrality (Gibbs-Donnan equilibrium⁶). These mechanisms ensure that sodium and its balancing anions, chloride and bicarbonate, are the mainstay of ECF osmolality, and potassium has the corresponding function in the ICF (Table 1.1).

Electrolyte	ECF (mmol/L)	ICF (mmol/L)	Total in body (mmol)
Sodium	140-145	10-18	3000-4000
Potassium	3.5-5.5	120-145	3000-4000
Calcium	2.2-2.5		25000-27000
Ionised calcium	0.9-1.3
Magnesium	0.7-1.2	15-25	900-1200
Chloride	98-106	2-6	3000-4000
Phosphate	0.7-1.3	8-20	30000-32000

The ECF is further divided into the intravascular (within the circulation) and the interstitial (extravascular fluid surrounding the cells) fluid spaces. The intravascular space (blood volume ≈6-7% of body weight) has its own intracellular component in the form of red (haematocrit ≈40-45%) and white cells and an extracellular element in the form of plasma (≈55-60% of total blood volume).

The intravascular and extravascular components of the ECF are separated by the capillary membrane, with its micropores, which allow only a slow escape rate of albumin (5%/h)⁷, which is then returned to the circulation via the lymphatics at the same rate, thereby maintaining equilibrium (Fig. 1.3). While the hydrostatic pressure within the circulation tends to drive fluid out, the oncotic pressure of the plasma proteins, e.g. albumin, draws fluid in and maintains the relative constancy of the plasma volume as a proportion of the ECF (Starling effect)⁸.

There is also a clinically important flux of fluid and electrolytes between the ECF and the gastrointestinal (GI) tract involving active secretion and reabsorption of digestive juices (Fig. 1.4). In health there is a constant flux between these various spaces and important physiological mechanisms ensure a constant relationship between them, which we may term the internal fluid balance^3,4.

The external fluid and electrolyte balance between the body and its environment is defined by the intake of fluid and electrolytes versus the output from the kidneys, the gastrointestinal tract, and the skin and lungs (insensible loss). Since the external and internal balances may be disturbed by disease, it is important to understand normal physiology in order to appreciate the disorders, which may occur in patients.

External balance

Values for the normal daily intake and output of fluid and electrolytes are shown in Tables 1.2 and 1.3. These are only an approximate guide and may have to be modified in the presence of excessive losses,

e.g. of water and salt through increased sweating and insensible loss in hot climates. They may also need to be modified in the presence of disease, e.g. gastroenteritis, which causes abnormal losses of fluid and electrolyte from the gastrointestinal tract (Fig. 1.3 and Table 1.4).

Intake (ml)		Output (ml)
Water from beverages	1200	Urine	1500
Water from solid food	1000	Insensible losses from skin and lungs	900
Metabolic water from oxidation	300	Faeces	100

Water	25-30 ml/kg/day
Sodium	0.9-1.2 mmol/kg/day
Potassium	1 mmol/kg/day

Secretion	Na+ (mmol/L)	K+ (mmol/L)	Cl– (mmol/L)
Saliva	40	20	40
Gastric juice	70-120	10	100
Bile	140	5	100
Pancreatic juice*	140	5	75
Small intestine	110-120	5-10	105
Diarrhoea (adult)	120	15	90
Sweat	30-70	0-5	30-70

*Pancreatic juice has a bicarbonate content of 50-70 mmol/l

Intake

Under normal circumstances most of our fluid intake is oral, but remember that all food contains some water and electrolytes and that water and carbon dioxide are end products of the oxidation of foodstuffs to produce energy. This metabolic water makes a small but significant contribution to net intake. Our drinking behaviour is governed by the sensation of thirst, which is triggered whenever our water balance is negative through insufficient intake or increased loss. It may also be triggered by a high salt intake, which necessitates the drinking and retention of extra water to maintain the ECF sodium concentration and osmolality in the normal range.

Although it may be blunted in the elderly, in most people the thirst mechanism ensures that intake matches the needs of bodily functions, maintaining a zero balance in which intake and output are equal and physiological osmolality of plasma (280-290 mOsm/kg) is maintained.

More than a century ago Claude Bernard coined the term ‘volume obligatoire’^1,2 to describe the mini- mum volume of urine needed to excrete waste products, such as urea, in order to prevent them accumulating in the blood. This concept implies that, if sufficient fluid has been drunk or administered to balance insensible or other losses and to meet the needs of the kidney, there is no advantage in giving additional or excessive volumes. Indeed, excessive intakes of fluid and electrolytes may be hazardous under certain circumstances (see below) and overwhelm the capacity of the kidney to excrete the excess and maintain normal balance. Salt and water retention causes oedema, which only becomes clinically apparent when the ECF has been expanded by at least 2.5-3 litres⁹.

Output

• Insensible loss: evaporation of water from the lungs and skin occurs all the time without us being aware of it. In temperate climates the amount so lost is 500-1000 ml/day. This may be even greater in a warm environment, during fever, or with exertion, when we produce additional sweat containing up to 50 mmol/L of sodium (and chloride). Patients with extensive burns can also have abnormally high insensible losses from the damaged tissues.
• Gastrointestinal losses: normally, the intestine absorbs water and electrolytes very efficiently so that fluid loss in the stool is as little as 100-150 ml/day, although, in the presence of disease this may be increased (Table 1.4 and Fig. 1.3).
• Kidney: this is the main organ for regulating fluid and electrolyte balance as well as excreting the waste products of metabolism, such as urea and creatinine. In this function, its activity is controlled by pressure and osmotic sensors and the resulting changes in the secretion of hormones. The modest daily fluctuations in water and salt intake cause small changes in plasma osmolality and volume which trigger both osmoreceptors and baroreceptors. This, in turn, causes changes in thirst sensation and also in renal excretion of water (via antidiuretic hormone) and salt (via aldosterone). If blood or ECF volumes are threatened by abnormal losses, baroreceptors are triggered (see below) and override the osmoreceptors. In the presence of large volume changes, therefore, the kidney is less able to adjust osmolality, which can be important in some clinical situations (Fig. 1.5).

• Water:

Organs, which sense the changes in osmolality of plasma (osmoreceptors), are located in the hypo- thalamus and signal the posterior pituitary gland to increase or decrease its secretion of vasopressin or antidiuretic hormone (ADH). Dilution of the ECF, including plasma, by intake of water or hypotonic fluid, causes ADH secretion to fall, so that the distal tubules of the kidney excrete more water and produce a dilute urine (this dilution requires the permissive effect of glucocorticoid upon the distal tubules and is, therefore, lost in adrenal insufficiency – one of the reasons for the hyponatraemia of Addison’s disease). Conversely, dehydration causes the ECF to become more concentrated. ADH secretion then rises and the renal tubules reabsorb more water, producing a concentrated urine. In response to dehydration, the normal kidney can concentrate urea in the urine up to a hundred-fold, so that the normal daily production of urea during protein metabolism can be excreted in as little as 500 ml of urine (volume obligatoire).

In the presence of dehydration, the urine to plasma urea or osmolality ratio is, therefore, a measure of the concentrating capacity of the kidney¹⁰. Age and disease can impair this function so that a larger volume of urine is required to excrete the same amount of waste products. Also, in the presence of a high protein intake or of increased protein catabolism, a larger volume of urine is needed to clear the resulting increase in urea production.

To assess renal function, therefore, measurement of both urinary volume and concentration (osmolality) are important, and the underlying metabolic circumstances should be taken into account. If serum urea and creatinine concentrations remain normal and unchanged over 24 hours, then fluid intake has been adequate, and the urinary ‘volume obligatoire’ has been achieved.

• Sodium (Na⁺):

Since the integrity of the ECF volume and its proportion of the total body water are largely dependent on the osmotic effect of sodium and its accompanying anions (e.g. Cl-, HCO₃ -), it is important that the kidneys maintain sodium balance within narrow limits. If salt depletion occurs, then the ECF, and with it the plasma volume falls. Pressure sensors in the circulation are then stimulated and these cause renin secretion by the kidney. This, in turn, stimulates aldosterone secretion by the adrenal gland, which acts on the renal tubules, causing them to reabsorb and conserve sodium. Under normal conditions, therefore, the urinary sodium excretion reflects underlying sodium balance. In the presence of disease, however, this relationship breaks down and reliance on urinary sodium measurements can give rise to errors in treatment (see below and Chapter14).

Conversely, if the intake of sodium is excessive, the renin-angiotensin-aldosterone system (RAAS) switches off, allowing more sodium to be excreted until normal balance is restored. The mechanism for salt conservation is extremely efficient and the kidney can reduce the concentration of sodium in the urine to <5 mmol/L. On the other hand, even in health, we are slow to excrete an excess salt load, possibly because our physiology has evolved in the context of a low salt environment and has not until modern times been exposed to excessive salt intake. The response of atrial natriuretic peptide to fluid infusions seems to be related more to volume (stretching of the right atrium) than sodium load per se¹¹.

The mechanism for maintaining sodium balance may become disturbed in disease, leading to sodium deficiency or, more commonly, to excessive sodium retention, with consequent oedema and adverse clinical outcome (see Chapter 16).

• Potassium (K⁺)

Although only a small proportion of the body’s potassium is in the extracellular space, its concentration has to be maintained within narrow limits (3.5-5.3 mmol/L) to avoid the risk of muscular dysfunction or potentially fatal cardiac events. This is achieved by exchange of potassium in the renal tubules for Na⁺ or H⁺, allowing more or less potassium to be excreted. In the presence of potassium deficiency, H⁺ ion reabsorption is impaired, leading to hypokalaemic alkalosis.

PATHOPHYSIOLOGY

Diseases such as gastroenteritis, diabetic ketoacidosis or Addison’s disease cause their own specific changes in fluid and electrolyte balance, but there are non-specific changes which occur in response to any form of injury or inflammation, which have important clinical implications, particularly for surgical patients.

Response to injury

In the 1930s, Cuthbertson^12,13 described the metabolic changes, which occur in response to injury (including surgery and sepsis), as an increase in metabolic rate and protein breakdown to meet the requirements for healing. These changes were later shown to be due to neuroendocrine and cytokine changes and to occur in three phases (Fig. 1.6).

The ebb or shock phase is brief and is modified by resuscitation. This gives way to the flow or catabolic phase, the length and intensity of which depends on the severity of injury and its complications. As inflammation subsides, the convalescent anabolic phase of rehabilitation begins. In parallel with these metabolic changes there are changes in water and electrolyte physiology^14-16. During the flow phase, there is an increase in ADH and aldosterone secretion leading to retention of salt and water with loss of potassium. These changes are exacerbated by any reduction in blood or ECF volume.

The normal, if somewhat sluggish, ability to excrete a salt and water load is further diminished, leading to the risk of ECF expansion and oedema if excessive salt and water are administered^14,17,18. The response to injury also implies that oliguria is a normal response to surgery, and does not necessarily indicate the need to increase the administration of salt and water or plasma expanders unless there are also indications of intravascular volume deficit, e.g. from postoperative bleeding¹⁹. Salt and water retention after injury can be seen teleologically as a mechanism to protect the ECF and circulating volume. It also explains why sick patients can be overloaded easily by excessive salt and water administration during the flow phase. Since water as well as salt is retained, it is also easy to cause hyponatraemia by giving excess water or hypotonic fluid. Even after uncomplicated elective surgery, the capacity of the kidney to dilute the urine is impaired for several days³. It is important, therefore, to administer crystalloids, not only in the correct volume but also with the appropriate electrolyte concentration. In the presence of the response to injury, the kidneys are unable to correct fully for errors in prescribing. This is further impaired in patients with acute kidney injury (AKI).

The convalescent phase of injury is characterised not only by the return of anabolism but also by a re- turning capacity to excrete any excess salt and water load that has been accumulated. These periods have been termed the ‘sodium retention phase’ and the ‘sodium diuresis phase’ of injury¹⁸.

Potassium (K⁺)

Potassium losses after surgery, sepsis and trauma are due not only to increased excretion in response to neuroendocrine mechanisms (e.g. the RAAS), but also to protein and glycogen catabolism. As intracellular protein is broken down and its constituent amino acids are released from cells, intracellular negative charges are lost and K⁺, with its balancing positive charges, passes into the ECF to be excreted. In situations where catabolism is extreme and renal function is impaired, the outflow of potassium from the cells may exceed the capacity of the kidney to excrete it, causing dangerous hyperkalaemia. Conversely, in the convalescent phase, as net intracellular protein and glycogen anabolism are restored, the cells take up potassium again and the patient’s potassium intake has to be increased to prevent hypokalaemia.

Transcapillary escape rate of albumin

The response to injury, inflammation and sepsis also results in an increase in the size of the pores in the capillary membrane and the transcapillary escape rate of albumin increases from about 5%/h in health to 13-15%/h⁷. These figures represent an average of all tissues in the body. There is, however, considerable variation from one organ to another, being higher in the liver than the skin, for example. This increase in albumin escape in response to inflammation can last from a few hours to several days, depending on the severity and duration of the underlying stimulus. Albumin leaks from the intravascular compartment into the interstitial space in association with water and sodium. This results in a net con- traction of the intravascular compartment and expansion of the interstitial space (Fig. 1.7). As the return of albumin to the circulation via the lymphatics is unchanged, the net result is an intravascular hypovolaemia with interstitial oedema.

Endothelial glycocalyx

The endothelial glycocalyx is a web of membrane-bound glycoproteins and proteoglycans on the luminal side of endothelial cells in the microcirculation, helping to maintain the function and integrity of the capillary-interstitial space interface. This interface can be damaged during the response to injury and inflammation and also by increased hydrostatic pressure caused by excessive intravenous fluid administration²⁰ (Fig. 1.8). Dysfunction of the endothelial glycocalyx in different organs secondary to inflammation or fluid resuscitation increases membrane permeability and the tendency to develop interstitial oedema.

CONCLUSION

Appropriate fluid therapy depends on an understanding of the underlying physiology and pathophysiology and also of external and internal fluid balance in health and disease.

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Chapter 2: AGEING AND FLUID BALANCE

INTRODUCTION

In the Western world the proportion of the population aged over 65 years is increasing steadily and in the UK is set to double by the year 2050²¹. This group also forms a high proportion of patients requiring surgery or presenting to hospital with fluid and electrolyte problems^22-24. Ageing is associated with di- minished reserve capacity of many organs, including the kidneys²⁵, causing increased susceptibility to both and water and electrolyte deficit and overload. Deficit of as little as 2% of total body water can cause significant impairment in physical, visual, psychomotor and cognitive performances²⁶. One study reported a 17% 30-day mortality in this group admitted to hospital with dehydration, and a 1-year mortality of 50%²⁷.

The hospital population increasingly reflects this demographic change. In contrast to younger patients, the elderly often have multiple comorbidities requiring more complex management and have decreased functional reserve of organs, e.g. heart, lungs and kidney. They also suffer from the consequences of polypharmacy. It is, therefore, particularly necessary to have an integrated approach to this vulnerable group of patients and to assess the combined effect of these factors (Tables 2.1 and 2.2).

PATHOPHYSIOLOGICAL BACKGROUND

With reductions of up to 50% in lean body mass in old age, total body water is reduced by 10-15% with an increased ECF:ICF ratio²². This and the renal structural and functional changes, associated with ageing, increase the risk that crystalloid administration can cause excessive ECF expansion, leading to peripheral and even pulmonary oedema. Older patients are also at risk of developing hyponatraemia from the ad- ministration of excessive volumes of hypotonic fluids. Renal changes, with the impaired ability to retain salt and water, also increase the risk of salt and water depletion, which is exacerbated by diuretics and by hot weather. In 2003, in France, a heat wave caused a 200% increase in mortality associated with fluid and electrolyte deficits in the older population²⁸.

Ageing is also associated with reduced serum concentrations of renin and aldosterone and a diminished renal tubular response to aldosterone. Atrial natriuretic peptide concentrations may be increased. These factors lead to a decreased capacity to maintain salt and water balance in the face of increased losses, or of diminished or excessive intake.

A blunted thirst response combined with reduced concentrating ability of the kidney increases the risk of developing a hyperosmolar state^29-31. This risk is even greater in those with dementia since they often forget to drink.

Both hyper- and hyponatraemia, determined by the relative balance between salt and water, are significant problems in older adults, with hyponatraemia being more common. In a hospital population, a seven-fold increase in mortality has been reported in those with hypernatraemia compared with age-matched controls³². Among those undergoing surgery, mortality in those with hypernatraemia was 12.7% compared with 2.3% in those with normal serum sodium concentrations³³. A prospective study of 200 older adults admitted to hospital in the UK showed that 37% were dehydrated on admission (serum osmolality >300 mOsm/kg) and were six times more likely to die in hospital than those with normal hydration²⁴. Hyponatraemia is an independent risk factor for bone fractures and for increased mortality in those admitted for orthopaedic surgery^34,35.

Impaired renal function also makes older adults more vulnerable to hyperkalaemia, with the risk being higher in those taking angiotensin converting enzyme (ACE) inhibitors. On the other hand, hypokalaemia is not uncommon, particularly among those on diuretic therapy.

DIURETICS AND OTHER DRUGS

Diuretics and other medications either singly or in combination have significant effects on salt and water balance. If used inappropriately, these drugs may precipitate a number of complications, many of which require hospital admission²².

Effects on salt and water balance

A high proportion of preventable hospital admissions among older adults are due to salt and water depletion caused by diuretics, the effects of which are often monitored inadequately. Patients should be educated in the management of these drugs and taught to stop them in the face of intercurrent illnesses³⁶, which reduce intake or increase losses of salt and water. Inappropriate continuation frequently precipitates fluid and electrolyte deficits. Patients receiving loop diuretics for heart failure may also be taught to monitor their fluid balance by daily weighing, taking the minimum dose required to maintain zero balance. This approach should be tailored to the individual patient’s circumstances and clinical features. Also, the high sodium content of many commonly prescribed drugs (e.g. antibiotics) can result in salt overload and should be taken into account when assessing fluid and electrolyte balance.

Effects on potassium balance

Medications such as ACE inhibitors, potassium sparing diuretics (e.g. spironolactone) and non-steroidal anti-inflammatory drugs interfere with potassium homeostasis and may result in hyperkalaemia.

SURGERY

Older adults undergoing surgery or being treated for acute trauma are at even greater risk than younger patients of developing salt and water depletion or excess. If possible, any such abnormalities should be corrected before surgery is undertaken since they impose an increased risk of morbidity and mortality³³. Perioperative management of such patients is described in Chapter 16.

CONCLUSION

When treating patients in the older age group one should have a high index of suspicion that a fluid and electrolyte abnormality may already exist, make a careful search for its cause and treat it appropriately. It is important to be aware of the diminished capacity of such patients to maintain fluid and electrolyte homeostasis in the face of challenges and to devise a management plan which takes account of this and seeks to prevent problems rather than having to treat them when they have already occurred.

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Chapter 3: DEFINITIONS

Much confusion in the diagnosis and treatment of fluid and electrolyte disorders is caused by loose and ambiguous terminology. The term ‘dehydration’, for example, meaning lack of water, is often used carelessly and imprecisely to include salt and water lack or, even more confusingly, intravascular fluid depletion. We, therefore, make a plea for the use of precise diagnostic terms, which indicate clearly the nature of the deficit or excess and the treatment required (e.g. salt and water depletion, plasma volume deficit, etc.).

Anabolism – the synthesis of large molecules from small ones, e.g. protein from amino acids or glycogen from glucose.

Catabolism – the breakdown of large molecules into small ones, e.g. protein to amino acids or glycogen to glucose.

Total body water (TBW) – percentage of body composition consisting of water, approximately 60% of body weight, less in obesity and more in infants. It is the sum of the intracellular and extracellular water in the body.

Intracellular fluid (ICF) volume – that part of the TBW contained within the cells, approximately 40% of body weight and 2/3^rds of TBW. Muscle cells contain 75% water and fat cells have <5% water.

Extracellular fluid (ECF) volume – that portion of the TBW outside the cells, approximately 20% of body weight and 1/3^rd of TBW, sustained osmotically mainly by sodium and its associated anions (e.g. Cl^– and HCO₃^–).

Interstitial fluid volume – that portion of the ECF outside the circulation and surrounding the cells.

Intravascular fluid volume

• the total blood volume consisting of red and white cells and plasma. May be estimated at approximately 6-7% of the body weight.
• the plasma volume is that part of the ECF contained within the circulation and supported oncotically by the plasma proteins, separated from the interstitial fluid by the capillary membrane. Comprises approximately 3-4% of the body weight.
• the effective circulatory volume refers to that part of the intravascular fluid volume that is in the arterial system at any one time (normally 700 ml in a 70 kg man) and is effectively perfusing the tissues.

Salt – in chemistry this is used to describe a whole family of compounds such as MgSO₄, FeSO₄, CaCl₂, etc. but colloquially and in clinical practice it has come to mean NaCl, and that usage will be followed in this book.

Electrolyte – a substance whose components dissociate in aqueous solution into positively (cation) and negatively (anion) charged ions. For example, sodium chloride in solution (saline), dissociates into Na+ and Cl-. Other electrolytes of physiological importance include Ca2⁺, Mg2⁺, K⁺, PO₄^2-, etc. Glucose is not an electrolyte as it does not dissociate in solution. In health the total number of positive charges balances the number of negative charges to achieve electrical neutrality.

Dehydration – the term ‘dehydration’ strictly means lack of water (hypertonic dehydration), yet it is also used colloquially to mean lack of salt and water (e.g. isotonic dehydration) or even more loosely to describe intravascular volume depletion. The terms ‘wet’ and ‘dry’ are applied to patients with similarly imprecise meaning. We make a plea for confining the use of dehydration to mean ‘water lack’ and for using unambiguous terms such as ‘salt and water depletion’, ‘blood loss’, ‘plasma deficit’, and so forth, since these are clear diagnoses indicating logical treatments. It may, however, be used legitimately to describe fluid deficit from sweating, remembering that a litre of sweat contains up to 50 mmol Na⁺ This may require salt as well as water replacement in tropical conditions. Severe dehydration can result in acute kidney injury.

Salt and water depletion – this is one of the commonest problems in hospital practice, arising from such conditions as diarrhoea and vomiting, ketotic and non-ketotic diabetic decompensation, and diuretic excess. The relative proportion of salt or water lack depends on the source of the loss and the amount of water, which the patient has consumed in order to assuage thirst: it is reflected in the serum concen- trations of sodium and chloride.

Intravascular volume depletion – this signifies a deficit in plasma or total blood volume, as in burns or haemorrhage, or a reduction in circulating volume secondary to a reduction in total ECF due to salt and water loss. The terms ‘plasma volume depletion’ or ‘blood volume deficit’ are even more specific.

Salt and water excess – this is most commonly iatrogenic, resulting from excessive administration of saline, but is, of course, a feature of congestive heart failure and other oedema producing conditions. It takes 2-3 litres of salt and water excess before the extracellular fluid is expanded sufficiently for oedema to become clinically apparent. Again, the relative proportions of salt and of water overload, but not the absolute amount of either, are reflected in the serum sodium and chloride concentrations.

Solution – fluid consisting of a solvent, e.g. water, in which a soluble substance or solute, e.g. sugar or salt, is dissolved.

Crystalloid – a term used commonly to describe all clear glucose and/or salt containing fluids for intra- venous use (e.g. 0.9% saline, Hartmann’s solution, 5% dextrose, etc.).

Colloid – a fluid consisting of microscopic particles (e.g. starch, gelatin or protein) suspended in a crys- talloid and used for intravascular volume expansion (e.g. 6% hydroxyethyl starch, 4% succinylated gelatin, 20% albumin, etc.).

Balanced crystalloid – a crystalloid containing electrolytes in a concentration as close to plasma as pos- sible (e.g. Ringer’s lactate, Hartmann’s solution, Plasmalyte 148, Sterofundin ISO, etc.). They should affect acid-base equilibrium minimally, when compared with 0.9% saline. Recently, the term “balanced” crys- talloid has been used to indicate intravenous fluids with low chloride (near physiological) content, as they do not produce the hyperchloraemic acidosis associated with 0.9% saline.

Buffer – a solution which resists changes in pH when acid or alkali is added to it. A buffer solution is an aqueous solution of a mixture of a weak acid and its conjugate base, or vice versa. Its pH changes very little when a small amount of strong acid or base is added to it. Buffer systems in the blood are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications. In nature, there are many systems that use buffering for pH regulation. For example, the bicarbonate buffering sys- tem is used to regulate the pH of blood.

Osmosis – this describes the process by which water moves across a semi-permeable membrane (per- meable to water but not to the solutes) from a weaker to a stronger solution until the concentration of solutes are equal on the two sides.

This force is termed osmotic pressure or, in the case of colloids e.g. albumin, oncotic pressure. It is pro- portional to the number of atoms/ions/molecules in solution and is expressed as mOsm/l (osmolarity) or mOsm/kg of solution (osmolality). E.g. the osmolarity of 0.9% saline is 308 mOsm/l, but the osmolality is 305 mOsm/kg (308 mOsm in 1.009 kg).

In clinical chemistry the term ‘osmolality’ is the one most often used. For example, out of approximately 280-290 mOsm/kg in extracellular fluid the largest single contributor is sodium chloride. This dissociates in solution and, therefore, its component parts Na⁺ and Cl^– exert osmotic pressure independently i.e. Na⁺ (140 mmol/kg), contributes 140 mOsm/kg, and Cl^– (100 mmol/kg) contributes 100 mOsm/kg. Additional balancing negative charges come from bicarbonate (HCO₃^–) and other anions. In the intracellular space K⁺ is the predominant cation (see below).

Because glucose does not dissociate in solution, each molecule, although much larger than salt, behaves as a single entity in solution and at a concentration of 5 mmol/L, contributes only 5 mOsm/kg to the total osmolality of plasma.

The cell membrane and the capillary membrane are both partially permeable membranes although not strictly semi permeable in the chemical sense (see below). They act, however, as partial barriers dividing the extracellular (ECF) from the intracellular fluid (ICF) space, and the intravascular from the interstitial space. Osmotic or oncotic shifts occur across these membranes, modified by physiological as well as pathological mechanisms.

Tonicity – the osmotic pressure or tension of a solution, usually relative to that of blood. Unlike osmotic pressure, tonicity is influenced only by solutes that cannot cross the membrane, as only these exert an effective osmotic pressure. Solutes able to cross the membrane freely do not affect tonicity because they will always be in equal concentrations on both sides of the membrane. Infusion solutions are, therefore, described as hypotonic, isotonic or hypertonic. E.g. 5% dextrose is isotonic at the point of infusion (in order to prevent haemolysis), but once its glucose content has been metabolised, it becomes hypotonic, giving a net gain of free water.

Free water – solute-free water (e.g. 1 L of 5% dextrose provides 1 L of free water as the dextrose is metabolised, whereas 1 L of 0.9% saline provides no free water).

Free water clearance is defined as the volume of plasma that is cleared of solute-free water per unit time. It is, therefore, greater in response to hypotonic fluid administration than in states of dehydration.

Anion gap – the difference between the plasma concentration of the major cation Na+ and the major anions Cl- and HCO -, giving a normal anion gap of 5-11 mmol/L. It is increased in metabolic acidosis due to organic acids as in diabetic ketoacidosis, lactic acidosis, renal failure, and ingested drugs and toxins.

Anion gap (mmol/L) = [Na⁺] – ([Cl^–] + [HCO₃^–])

The anion gap is normal in hyperchloraemic acidosis (e.g. after excess 0.9% saline administration). It is, therefore, useful in the differential diagnosis of metabolic acidosis, although specific measurement of organic acids such as β-hydroxy butyrate or lactate may also be necessary to define the problem.

Strong ion difference (SID) – Stewart³⁷ has described a mathematical approach to acid-base balance in which the strong ion difference (SID (mmol/L)=[Na⁺]+[K⁺]-[Cl⁻]) in the body is the major determinant of the H⁺ ion concentration. A decrease in the strong ion difference is associated with a metabolic acidosis, and an increase with a metabolic alkalosis. A change in the chloride concentration is the major anionic contributor to the change in H+ homoeostasis. Hyperchloraemia caused by a saline infusion, therefore, will decrease the strong ion difference and result in a metabolic acidosis.

e.g. If Na⁺ is 140 mmol/L, K⁺ is 4 mmol/L and Cl^– is 100 mmol/L, the SID is 44 mmol/L. The normal range is 38-46 mmol/L.

Base excess – Base excess is defined as the amount of strong acid that must be added to each litre of fully oxygenated blood to return the pH to 7.40 at a temperature of 37°C and a P_aCO₂ of 40 mmHg (5.3 kPa). A base deficit (i.e., a negative base excess) can be correspondingly defined in terms of the amount of strong base that must be added.

Acidaemia and Alkalaemia – An increase in the H⁺ ion concentration or a decrease in the pH is called acidaemia; a decrease in the H⁺ ion concentration or an increase in the pH is called alkalaemia.

Acidosis and Alkalosis – Processes that tend to raise or lower the H⁺ ion concentration are called acidosis and alkalosis respectively. These may be respiratory, metabolic or a combination of both. CO₂ retention causing a rise in P_aCO₂ in respiratory failure leads to respiratory acidosis, and hyperventilation with a consequent lowering of P_aCO₂ leads to respiratory alkalosis. Accumulation of organic acids such as lactate or β-hydroxybutyrate or of mineral acidic ions such as chloride cause a metabolic acidosis in which arterial pH falls below 7.4, HCO₃^– is reduced and P_aCO₂ falls as the lungs attempt to compensate by blowing off more CO₂. This is called a compensated metabolic acidosis. Similarly, ingestion of alkalis such as HCO₃^– or loss of gastric acid cause a rise in pH and a metabolic alkalosis.

External balance – is the difference between intake of fluid and electrolytes from food and drink (or enteral or parenteral fluid therapy) and loss via the kidneys, gastrointestinal tract, skin and lungs.

Internal balance – is the redistribution of fluid and electrolytes between different body compartments (e.g. between the intravascular and interstitial space or between ECF and ICF). It also includes shifts into spaces such as the pleural and peritoneal cavities or into the gastrointestinal tract due to pooling of secretions as in postoperative ileus or intestinal obstruction.

Insensible loss – loss from the skin by sweat or evaporation, from the lungs as water vapour or from wounds by exudation or evaporation. Under normal clinical conditions it is difficult to quantify such losses, except by changes in weight. One of the major limitations of fluid balance charts is that this loss of fluid can only be estimated and not quantified. This could range from 500-1000 ml/day, or even higher, depending on ambient temperature, body temperature, respiratory rate, burn surface area, etc.

Estimated glomerular filtration rate (eGFR) – is a mathematically derived value based on a patient’s serum creatinine concentration, age and sex. This is usually calculated by the laboratory analysing the blood sample and reported along with the serum creatinine result. “Normal” GFR is usually >90 ml/min/1.73 m². (Note the correction for body surface area “per 1.73 m²” which is important for certain patient groups, e.g. amputees, extremes of body habitus.)

Acute kidney injury (AKI) – a rapid reduction in kidney function occurring over hours or days, resulting in a rise in blood urea and creatinine and disturbance of fluid and electrolyte balance³⁸. New definitions and staging systems for AKI are based on rises in serum creatinine or reductions in urine output (see Chapter 10).

Acute kidney disease (AKD) – the concept of AKD is relatively new and refers to the scenario where there is a decrease in kidney function over a period of less than three months, and the change in creatinine value does fit the definition of AKI. The following criteria have been proposed; a reduction in eGFR by >35% or an increase in creatinine by >50% in <3 months³⁹.

Chronic kidney disease (CKD) – a slow and prolonged reduction in kidney function that is sustained for more than 3 months³⁹. There is an established definition and staging system for CKD based upon the level of eGFR and albuminuria (see Chapter 11).

Sepsis – defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality⁴⁰.

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Chapter 4: ACID-BASE BALANCE

INTRODUCTION

Maintenance within narrow limits of the normal acid base composition of the ‘milieu interieur’ is essential for the optimal function of tissues^10,41-43. The kidneys together with the lungs and liver play an essential role in the maintenance of normal acid-base balance and arterial blood pH (Table 4.1). The kidneys remove acid and regenerate bicarbonate, the lungs can regulate the removal of acid (CO₂) by varying respiratory rate and the liver removes and recycles lactate. Therefore, patients with advanced CKD stage 4-5 (eGFR <30 ml/min/1.73 m²), liver disease or underlying respiratory disease are at increased risk of developing acid-base abnormalities at times of acute illness.

pH	7.35-7.45
PaO2 (kPa)	10.7-16.0
PaCO2 (kPa)	4.7-6.0
HCO3 (mmol/L) –	22-26
Base excess (mmol/L)	-2 – +2
Anion gap (mmol/L)	5 – 11

A normal blood pH of 7.35-7.45 is maintained by different buffering systems which include the blood, kidney, lung and liver buffering system described below.

The blood buffering system, which is dependent upon

• bicarbonate (HCO₃^–)

• the relative proportion of carbonic acid from CO₂ and of HCO₃^– is defined by the Henderson-Hassel- bach equation^44,45. Note that the pH is determined by the ratio of HCO₃^– to CO₂.

• haemoglobin
• phosphate (organic and inorganic)
• bone and its calcium salts

The kidney buffering system which

• controls hydrogen H⁺ and HCO₃^– excretion or reabsorption as well as the conversion of ammonia (NH₃) to ammonium (NH₄⁺) in the urine.

The lung buffering system, which controls

• CO₂ in the blood, increasing expired CO₂ when more is produced or to compensate for metabolic acidosis.

The liver buffering system which

• removes and recycles the large amounts of lactate produced by anaerobic respiration (Cori cycle).

Disease states can disrupt this finely balanced system resulting in a dangerously low (pH <7.1) or dangerously high pH (pH >7.6). Specific patient management will depend upon the clinical status of the patient and the underlying cause of the acid-base disorder. This chapter will provide a simple description of the most common forms of the simple acid-base disorders. Expert advice should be sought if it is suspected that the patient has a more complex form of acid-base disorder.

APPROACHES TO ACID-BASE BALANCE

There are essentially two different ways to approach acid-base disorders.

• The traditional Schwartz-Bartter approach, which accepts the Bronsted-Lowry definition of acids as proton donors and bases as proton acceptors. The hydrogen ion concentration is a function of the ratio between the carbon dioxide (CO₂) and the serum bicarbonate (HCO₃^–). This traditional approach utilises the anion gap calculation to classify acid-base disturbances and is the method used in this chapter.

• The Stewart approach^37,46, termed the Strong Ion Difference (SID), is based on the principle that the serum bicarbonate concentration does not alter blood pH. This approach is favoured by intensivists and anaesthetists and is described separately towards the end of this chapter.

CLINICAL PRESENTATION

It is important in every acutely ill patient to consider whether there may be an underlying acid-base disturbance. Serum bicarbonate and chloride are not standard components of all urea and electrolyte (U&E) reports and may have to be specifically requested. Severe acidaemia (pH <7.1) results in impaired cardiac function and vascular tone. Severe alkalaemia (pH >7.6) results in irritability of cardiac and skeletal muscle.

Conditions commonly causing acid-base disorders include:

• vomiting/diarrhoea
• shock
  • cardiogenic
  • septic
  • hypovolaemic
• acute kidney injury
• respiratory failure
• altered neurological status
  • coma
  • seizures
• decompensated diabetes mellitus
• hypokalaemia or hyperkalaemia
  • potassium metabolism is intimately linked to acid-base balance
• prolonged and excessive infusions of 0.9% saline causing hyperchloraemic metabolic acidosis (as 0.9% saline has a chloride concentration that is 1.5 times that of plasma)

If an acid-base disturbance is suspected from clinical features, the following blood tests should be per- formed initially:

• Urea, creatinine and electrolytes (U&Es)
• Bicarbonate
• Chloride
• Glucose
• Arterial blood gases (including lactate)

These investigations can then be used in a step-by-step approach to identify the type of acid-base disorder

• assess the pH to determine whether acidaemia or alkalaemia
• a change in HCO₃^– and base excess (BE) indicates a metabolic process
• a change in P_aCO₂ indicates a respiratory process
• determine whether
  • simple disorder, i.e. either metabolic or respiratory process alone
  • mixed disorder, i.e. a combination of a metabolic and respiratory process. There will be evidence of compensatory changes in either HCO₃^– or P_aCO₂
• calculate the anion gap
  • determined primarily by negative charge on serum proteins, particularly albumin
  • normal anion gap = 5-11 mmol/L

Anion Gap = [Na⁺] – ([HCO₃^–] + [Cl^–])

• in the clinical setting of hypoalbuminaemia the normal anion gap is adjusted downward by 2.5 mmol/L for every 10 g/L reduction in serum albumin concentration
  • an increase in anion gap indicates a tendency towards acidosis and a decrease a tendency towards alkalosis.

Simple acid-base disorders

Table 4.2 demonstrates simple acid-base disorders in terms of the primary change in bicarbonate or car- bon dioxide, the compensatory changes that occur and the effect on pH. By a simple rule of thumb, in simple acid-base disorders the acid-base buffer pair change in the same direction. If they change in the opposite direction the disorder must be mixed.

	Primary change	Primary change in pH	Physiological compensation
Metabolic acidosis	↓ HCO3–	↓ pH	↓ PaCO2
Metabolic alkalosis	↑ HCO3–	↑ pH	↑ PaCO2
Respiratory acidosis	↑ PaCO2	↓ pH	↑ HCO3–
Respiratory alkalosis	↓ PaCO2	↑ pH	↓ HCO3–

Causes of simple acid-base disorders

The cause of an acid-base disorder is often apparent from the clinical presentation. Metabolic acidosis is best considered as associated with a high anion gap (Table 4.3) or a normal anion gap (Table 4.4).

‘High anion gap’ metabolic acidosis – can be caused by four broad categories of disorders including ketoacidosis, lactic acidosis, poisonings, AKI or CKD.

• Ketosis occurs when there is a lack of insulin or hypoglycaemia. To compensate, fatty acids are oxidised to produce energy resulting in the production of ketoacids as a by-product.
  • Severe ketoacidosis occurs secondary to insulin deficiency (see Chapter 14)
  • Moderate ketosis may also occur with prolonged starvation or in alcoholics
• Lactic acidosis is subdivided into
  • Type A lactic acidosis – secondary to insufficient oxygen delivery to the tissues
    • hypovolaemic shock
    • cardiogenic shock
    • septic shock
  • Type B lactic acidosis – impaired gluconeogenesis causing inability to clear lactate
    • liver failure
    • metformin
• Drug toxicity can be subdivided into
  • ethylene glycol/methanol
    • metabolism generates glycolate from ethylene glycol and formate from methanol
    • associated with an elevated osmolal gap
    • measured serum osmolality – calculated osmolality
    • calculated osmolality = 2 × [Na+] + glucose + urea
    • intoxication likely if measured serum osmolality – calculated osmolality >25 mOsm/kg
    • clinically presence of calcium oxalate crystals in the urine suggests ethylene glycol toxicity
  • salicylates
    • may result in a metabolic acidosis, respiratory alkalosis or a mixed acid-base disorder
• Kidney disease
  • chronic kidney disease and acute kidney injury result in reduced
    • excretion of the daily acid load (sulphates, phosphates and organic anions)
    • regeneration of bicarbonate

‘Normal anion gap’ (hyperchloraemic) metabolic acidosis – can be caused by excess saline infusion, or by gastrointestinal or renal bicarbonate loss. Rarer causes include inorganic acid intake.

• Gastrointestinal bicarbonate loss results from
  • diarrhoea and external fistulae from the pancreas and small bowel
  • increased chloride absorption occurring as a compensatory mechanism and resulting in a hyperchlo- raemic metabolic acidosis with a normal anion gap
• Renal bicarbonate loss results from
  • renal tubular acidosis (RTA), conditions that are caused either by failure to reabsorb bicarbonate from the proximal tubule (type II RTA) or bicarbonate wasting from the distal tubule (type I RTA)
  • acetazolamide (carbonic anhydrase inhibitor) which inhibits bicarbonate reabsorption

Metabolic alkalosis – can occur in association with fluid depletion or mineralocorticoid excess (Table 4.5). In metabolic alkalosis associated with fluid depletion there is loss of fluid rich in H⁺ or Cl^– from the stomach, kidneys or skin. In the absence of fluid depletion, a metabolic alkalosis may occur in hyperaldosteronism, due to enhanced renal H⁺ secretion.

Respiratory acidosis – may occur acutely due to respiratory depression secondary to drugs or neurological damage, respiratory muscle weakness, chest injury or acute airway obstruction. In some cases of chronic obstructive airway disease P_aCO₂ may also be permanently elevated, usually partially compensated by an increase in plasma HCO₃^–.

Existing respiratory disease may be exacerbated perioperatively by atelectasis, respiratory infection, retained sputum, abdominal distension, splinting of the diaphragm, pain from the wound or high doses of opiates. Epidural analgesia may be advantageous in such conditions. In severe cases, particularly those with prior lung disease, bronchial suction and mechanical ventilation may be necessary. Early mobilisation and chest physiotherapy is also vital in many cases.

Respiratory alkalosis – is due to hyperventilation, causing a low P_aCO₂ and in chronic cases, some com- pensatory reduction in HCO₃^–. It may be iatrogenic due to deliberate or mistakenly overenthusiastic artificial ventilation, or secondary to hyperventilation from anxiety or distress. It sometimes causes paraesthesiae, tetany and chest pain.

MANAGEMENT

The principles of management involve correcting any abnormalities of fluid and electrolyte balance (e.g. hypovolaemia, salt and water deficit). The underlying cause for the acid-base disorder (e.g. ketoacidosis, AKI, sepsis) must be diagnosed and managed promptly. In general, specific therapy (e.g. bicarbonate administration for acidosis) to correct the [HCO₃^–] or P_a CO₂ is only contemplated if the acid-base disorder is affecting organ function or if the pH is <7.1 or >7.6.

Patients identified as having an AKI and metabolic acidosis secondary to ethylene glycol or methanol in- toxication need immediate referral to the renal team for consideration of intermittent haemodialysis to remove the toxin. Fomepizole, an alcohol dehydrogenase inhibitor is the preferred first line therapy to prevent the metabolism of ethylene glycol or methanol to their respective toxic metabolites. Additional management should be guided by advice from a poisons centre, but may include the intravenous infusion of alcohol (ethanol) to prevent the breakdown of ethylene glycol and methanol to their toxic metabolites by alcohol dehydrogenase if fomepizole is not available.

Mixed acid-base disorders

These are defined as the presence of more than one cause (e.g. metabolic and respiratory). The patient’s history or a lesser or greater than predicted compensatory respiratory or renal response may raise suspicions of mixed acid-base disorder.

A normal pH in the setting of substantial changes in both serum HCO₃^– or arterial P_aCO₂ indicates a mixed- acid base disorder is present.

Stewart approach to acid-base disorders

The Stewart approach³⁷, termed the Strong Ion Difference (SID), is based upon the central tenet that serum bicarbonate does not alter blood pH. Stewart defined acids as ions that shift the dissociation equi- librium of water to a higher concentration of H⁺ and a lower concentration of OH^–.

The SID is the difference between the completely dissociated cations and anions in the plasma. It is defined as the difference between the sum of the strong cations, Na⁺, K⁺, Ca²⁺ and Mg²⁺ and the sum of the net charge of the major strong cations, Cl^– and lactate.

SID = [Na⁺ + K⁺ + Ca²⁺ + Mg²⁺] – [Cl^– + lactate] = 38-46 mmol/L

An increase in the SID is associated with an increase in blood pH, an alkalosis, e.g. vomiting leads to a loss of chloride and a decrease in serum chloride levels resulting in an increase in SID and alkalosis. The Stewart approach, therefore, explains the alkalosis associated with vomiting as excessive loss of chloride.

A decrease in SID is associated with a decrease in blood pH, an acidosis, e.g. the excessive infusion of saline results in an increase in [Cl-] and, therefore, a decrease in SID and an acidosis. The Stewart approach, therefore, explains the hyperchloraemic metabolic acidosis associated with excessive saline infusion by the gain of chloride.

Conclusion

An acid-base disorder should be suspected in all seriously ill patients or those with an indicative history. It should be fully investigated to determine whether the changes have a metabolic or respiratory cause or a combination of the two. The aim of treatment should be to correct the underlying cause of the acid- base disorder, e.g. diabetic ketoacidosis. In severe cases it may be necessary in the short term to restore blood biochemistry towards normal, e.g. with bicarbonate infusions in acidosis.